The aetiology of any neuropathology is a complex interplay of genetic, physiological and environmental factors. Effective treatment of these conditions will ultimately depend upon the understanding of the cognate genes and their products. In recent years, it has become apparent that large families of related genes are responsible for the regulation of neuropathologies involving anxiogenic peptides. The identification and characterization of these gene families and how they interact is an essential step towards ultimately effectively treating the pathology. The aberrant regulation of neuronal growth can manifest as a variety of pathological conditions depending upon the age. Deficits in neuronal growth in foetal or neonatal animals can cause such diseases as learning deficits, mental retardation, autism, or schizophrenia. At later ages in juvenile individuals it may manifest as affective disorders such as panic disorder, depression, anorexia nervosa, obsessive-compulsive disorder later in adults. In adults such neuronal growth problems could lead to neurodegenerative illnesses such as Alzheimer's Disease or Parkinsons's Disease.
The onset of mood disorders, such as depression or post traumatic stress disorder, involve the altered function of multiple loci in the brain that regulate emotionality, memory and motivation (Manji et al., 2001; Drevets, 2001; Nestler et al., 2002). However, many of the cellular signaling molecules that mediate communication within and between these regions are unknown, leading to an incomplete understanding of the origin of such disorders.
Many neuropeptides show the presence of three or four paralogous structures as evidenced by the neuropeptide Y (NPY) (Larhammar, 1996a,b), proopiomelanocortin (POMC) (Danielson, 2000) and recently, the corticotropin releasing factor (CRF) family (Vale et al., 1981, Vaughan et al., 1995; Lovejoy and Balment, 1999; Lewis et al., 2001 Reyes et al., 2001; Hsu and Hseuh, 2001).
A family of neuronal cell surface proteins has been identified that are predominantly expressed in the nervous system. These proteins have been named teneurins (Rubin et al, Developmental Biology 216, 195-209 (1999)). Four basic teneurins have been identified Ten M1, Ten M2, Ten M3, and Ten M4. The Ten-M or Odz proteins were originally discovered in Drosophilia (Levine et al., 1994; Baumgartner et al., 1994) and are presently the only known example of a pair-rule gene that is not a transcription factor. The Ten-M gene is initially activated during the blastoderm stage, then down regulated before being expressed at later stages. The highest levels of Ten-M occur in the central nervous system where the protein occurs preferentially on the surface of axons (Levine et al., 1994; Levine et al, 1997). Mutations of the ten-M/Odz gene result in embryonic lethality (Baumgartner et al., 1994; Levine et al., 1994).
Four Ten-M paralogous genes, called Teneurins, exist in vertebrates and encode a Type II transmembrane protein where the carboxy terminus of the protein is displayed on the extracellular face of the cell (Oohashi et al., 1999). The teneurin proteins are about 2800 amino acids long. There is a short stretch of hydrophobic residues at 300 to 400 amino acids after the amino terminus that appear to act as the membrane spanning site. In the cytoplasmic N-terminal portion, is a conserved proline-rich SH3-binding site indicating a potential site where by they bind other proteins. Evidence suggests that the protein may be cleaved from the membrane at a Furin-like cleavage motif (RERR) located around residue 528 in teneurin 2 (Rubin et al., 1999). However, this motif is not present in the other paralogues and therefore a soluble version of the protein may not occur for all paralogues. There are a series of cysteine-rich EGF-like repeats carboxy terminal to this. Homodimerization occurs between Ten M1 forms via interaction between EGF-like modules 2 and 5 (Oohashi et al., 1999).
The ten-m gene appears to be upregulated by stressors. Wang et al (1998) showed that a ten-M like transcript, named DOC4 (downstream of chop) in mammalian cells was upregulated by the transcription factor GADD153/CHOP. This transcription factor is induced by several types of cellular stressors including UV light, alkylating agents or conditions triggering endoplasmic reticulum (ER) stress responses, such as, deprivation of oxygen, glucose or amino acids, or interference of calcium flux across the ER membrane (Zinszner et al, 1998). GADD153 is a small nuclear protein that dimerizes with members of the C/EBP family of transcription factors (Ron and Habener, 1992). It does not appear to homodimerize. GADD153 undergoes a stressor inducible phosphorylation by a p38-type MAP kinase which also enhances the transcriptional activation of GADD153 (Wang et al., 1996). High expressions of GADD153 will lead to cell cycle arrest (Zhan et al. 1994). These studies suggest that the teneurin gene may play a significant role in the regulation of the stress response of neurons and other cells.
Overexpression of teneurin 2 into the mouse neuroblastoma cells (Nb2a) augmented the amount of neurite outgrowth and a tendency to enlarge the growth cones. The number of filamentous actin-containing filopodia was also enhanced in the teneurin 2 overexpressing cells (Rubin et al., 1999). The expression of the teneurin genes have been examined in embryonic zebrafish (Mieda et al, 1999), chicken (Rubin et al., 1999) and mouse (Ben-Zur et al., 2000) although their expression patterns have not been finely resolved. The transcripts are found in a number of peripheral tissues but are found predominantly in the central nervous system. In the embryonic chicken brain, teneurin 1 and 2 are expressed in the retina, telencephalon, the optic tectum and the diencephalons. The mRNA for teneurin 1 was found mainly in the intermediate zone of the dorsal thalamus whereas teneurin 2 was found in the intermediate zone of the thalamus (Rubin et al., 1999). In zebrafish, teneurin 4 is faintly expressed throughout gastrulation, although there is no teneurin 3 expression. Teneurin 3 expression begins at the notochord and the somite around the tailbud stage. In later stages (14 h post fertilization), teneurin 3 is expressed in the somites, notochord and brain while teneurin 4 expression was confined to the brain. Teneurin 3 becomes defined within the optic vesicles and region covering the caudal diencephalons and mesencephalon with the expression strongest in the anterior mesencephalon. Teneurin 4 has its strongest expression toward the midbrain hindbrain border. By 23 h post fertilization, teneurin 3 is expressed in the dorsal part of the tectal primordium and the ventral midbrain while teneurin 4 is expressed in the ventral primordium (Mieda et al., 1999).
Neuropathological conditions tend to be complex and not very well understood. As such, there is a need to better understand the mechanisms involved and to develop a method of diagnosis and treatment of said conditions. There is also a need for the identification and design of therapeutic compounds for said conditions.